INSERM, U871, 69003 Lyon.
J Hepatol. 2011 Feb;54(2):288-99. doi: 10.1016/j.jhep.2010.06.033. Epub 2010 Sep 16.
BACKGROUND & AIMS: We previously reported the frequent overexpression of the FZD7 membrane receptor in hepatocellular carcinoma (HCC) and its role for controlling cancer phenotype. Herein, this study aimed at assessing the anticancer properties of compounds inhibiting FZD7 activity by disrupting its binding with the cytosolic Dishevelled (DVL) adaptator.
We have designed small interfering peptides (RHPDs) that are able to enter within cells and to competitively antagonize the binding of FZD7 to the PDZ domain of DVL. Their anti-neoplastic properties were assessed in vitro on a panel of human HCC cell lines and in vivo on the SV40-TAg transgenic mouse model of HCC.
We have shown that RHPDs decrease cell viability via apoptosis depending on their affinity for PDZ, with a therapeutic index between cancerous and non-cancerous cells. RHPD properties were linked to β-catenin degradation and PKCδ activation. In transgenic mice, intra-tumor injection of RHPDs inhibited HCC progression.
We have completed a proof-of-concept showing that in vitro and in vivo the pharmacological inhibition of FZD7 displays anti-cancerous properties against HCC. The mechanisms can involve β-catenin and PKCδ modulations. Further studies are warranted to design protocols showing the compatibility with systemic in vivo applications.
我们之前报道了 FZD7 膜受体在肝细胞癌（HCC）中频繁过表达，并证实其对控制癌症表型具有重要作用。本研究旨在评估通过破坏 FZD7 与其胞质 Dishevelled（DVL）衔接蛋白的结合来抑制 FZD7 活性的化合物的抗癌特性。
我们设计了能够进入细胞并竞争性拮抗 FZD7 与 DVL PDZ 结构域结合的小干扰肽（RHPDs）。在一系列人 HCC 细胞系上评估其体外抗肿瘤特性，并在 SV40-TAg 转基因 HCC 小鼠模型上评估其体内抗肿瘤特性。
我们发现，RHPDs 通过凋亡降低细胞活力，其对 PDZ 的亲和力决定了治疗指数，在癌细胞和非癌细胞之间存在治疗指数。RHPD 的特性与β-catenin 降解和 PKCδ 激活有关。在转基因小鼠中，RHPD 瘤内注射抑制 HCC 进展。
我们完成了一项概念验证研究，表明体外和体内抑制 FZD7 的药理作用对 HCC 具有抗癌作用。其机制可能涉及β-catenin 和 PKCδ 的调节。需要进一步的研究来设计显示与全身体内应用兼容性的方案。
